tbuckley/cabot-search huggingface dataset:
P695: PROGNOSTIC IMPACT OF ASXL1 MUTATIONS IN CHRONIC PHASE CML
Authors: A. Bidikian, H. Kantarjian, E. Jabbour, N. Short, F. Ravandi, G. Issa, K. Sasaki
Journal: HemaSphere (2022)

Background: While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about mutations in genes frequently involved in myeloid malignancies. Aims: To characterize the clinical impact of mutations in non-ABL1 genes in CP-CML. Methods: We identified 66 patients (pts) with CP-CML where targeted next generation sequencing was performed at our institution. This panel included 81 genes recurrently mutated in myeloid malignancies. Event-free survival (EFS) was measured from treatment initiation to the time of an event defined as loss of hematologic response, loss of major cytogenetic response (MCyR), transformation to accelerated or blast phase and lack of MCyR after 12 months of treatment. Failure-free survival (FFS) was measured similarly with the additional events of drug discontinuation due to lack of response or adverse effect. We subsequently performed univariate and multivariate analyses for survival. Results: The median age of pts was 61 years (18 – 80 years) and 48% were female. The most common first line therapy in these patients was Dasatinib (52%), followed by Imatinib (19%), Dasatinib + Venetoclax (16%), Nilotinib (8%), Bosutinib (3%) and Ponatinib (2%). The distribution of evaluable patients to low, intermediate and high Sokal risk groups was 22%, 62% and 16%, respectively. Non-ABL1 mutations were found in 22/66 patients (33%), with 5 (8%) of pts with at least 2 mutations. Most common mutations involved ASXL1 (8/66 pts; 12%), DNMT3A (4/66 pts; 6%) and RUNX1 (3/66 patients; 5%). Mutations in ASXL2, CALR, EZH2, GNAS, IDH2, SF3B1, SMC3, SRSF2, STAG2 and SUZ12 were detected at least once. Unlike mutations in other genes, mutated ASXL1 was associated with worse EFS compared with wild-type with a median of 33 vs 88 months (P = 0.009) (Figure 1A) and worse FFS with medians of 32 vs 58 months, respectively (P = 0.05) (Figure 1B). There was no difference in overall survival by mutational status (Figure 1C). In a multivariate analysis including all baseline prognostic variables, mutated ASXL1 was independently associated with worse EFS with a hazard ratio of 5.94 (95% CI 1.25 – 28.21; P = 0.03). There was no difference in rates of cytogenetic and molecular responses by mutational status. However, time to achievement of response was longer in patients with mutated ASXL1 albeit not statistically significant. (Figure 1D) Image:Summary/Conclusion: Mutations in ASXL1 are associated with delayed responses and worse outcomes when detected in chronic phase CML.
Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5
Authors: Nicole P Hachmann, Jessica Miller, Ai-Ris Y Collier, John D Ventura, Jingyou Yu, Marjorie Rowe, Esther A Bondzie, Olivia Powers, Nehalee Surve, Kevin Hall, Dan H Barouch
Journal: New England Journal of Medicine (2022)

To the Editor: In recent months, multiple lineages of the omicron (B.1.1.529)variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, 1 with subvariants BA.1 and BA.2 showing substantial escape from neutralizing antibodies. 2-5Subvariant BA.2.12.1 is now the dominant strain in the United States, and BA.4 and BA.5 are dominant in South Africa (Fig. 1A).Subvariants BA.4 and BA.5 have identical sequences of the spike protein.We evaluated neutralizing antibody titers against the reference WA1/2020 isolate of SARS-CoV-2 along with omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated and boosted with messenger RNA vaccine BNT162b2 (Pfizer-BioNTech) and in 27 participants who had been infected with the BA.1 or BA.2 subvariant a median of 29 days earlier (range, 2 to 113) (Tables S1 andS2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).In the vaccine cohort, participants were excluded if they had a history of SARS-CoV-2 infection or a posi-The New England Journal of Medicine Downloaded from nejm.
A Challenge to Respiratory Syncytial Virus Illness in Adults
Authors: Marie R. Griffin
Journal: New England Journal of Medicine (2022)

Respiratory syncytial virus (RSV) has been increasingly recognized as a cause of serious lower respiratory tract infections in older adults as well as in young children. Each winter in the United States, RSV-associated respiratory infections develop in 3 to 10% of adults.1 Like influenza, these infections are often more severe and prolonged than the "common cold." The incidences of RSV-associated illness and death among adults increase with advancing age and the prevalence of coexisting conditions, such that approximately 1 or 2 per 1000 U.S. adults 65 years of age or older are hospitalized with RSV-associated pneumonia or exacerbation of underlying . . .
Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women
Authors: Chen Liang, Hsin-Fang Chung, Annette J Dobson, Kunihiko Hayashi, Yvonne T van der Schouw, Diana Kuh, Rebecca Hardy, Carol A Derby, Samar R El Khoudary, Imke Janssen, Sven Sandin, Elisabete Weiderpass, Gita D Mishra
Journal: BMJ (2022)

To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes.
P1153: LONG-TERM SURVIVAL OUTCOMES OF PATIENTS WITH PRIMARY OCULAR ADNEXAL MALT LYMPHOMA: A LARGE SINGLE-CENTER COHORT STUDY
Authors: Y. Liang, R.-Y. Fu, X. Li, Y.-S. Piao, J.-M. Ma, L. Wang
Journal: HemaSphere (2022)

Background: Primary ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (OAML) is a rare subtype of non-Hodgkin’s lymphoma, and no consensus has been defined concerning the optimal treatment strategies. Aims: This study aims to investigate the associations of disease characteristics and different treatments with long-term outcomes of patients with localized OAML. Methods: A large retrospective cohort study was conducted in a single-center of China, and 166 patients with newly diagnosed primary localized OAML between April 2008 and August 2021 were enrolled in our analysis. Detailed data of disease characteristics at diagnosis and treatments were collected for all patients, and treatment response was evaluated at one month after therapy and every six months thereafter. We compared treatment response and progression-free survival (PFS) among patients with different characteristics and treatments. Results: Of the 166 patients, 52 received complete resection of neoplasm, whereas 114 had residual lesion after surgery. Among the 114 patients, 61 underwent watchful waiting and 53 received further treatment including localized radiotherapy, chemotherapy (including immunochemotherapy), or combined radiotherapy and chemotherapy. Median follow-up of these patients was 49 months (range: 2-156). A total of 31 patients had disease progression or relapse during follow-up, including four patients with such event more than five years after initial treatment. The 5-year PFS was 73.9%, 70.6% and 85.9%, whereas the 10-year PFS was 69.3%, 59.2% and 79.3%, among patients with complete resection of neoplasm, patients in the watchful waiting group and patients with further treatment, respectively. Patients with further treatment had longer PFS, compared with patients in the watchful waiting group (P=0.011), while no difference in PFS was noted between patients with further treatment and patients with complete resection of neoplasm (P=0.127). Bilateral involvement at diagnosis was associated with significantly inferior PFS (P=0.029), whereas age, IPI score, or TNM staging was not associated with PFS. No serious adverse reaction was reported among patients with further treatment. Image:Summary/Conclusion: Bilateral involvement was associated with poor prognosis. Among patients with residual lesions after surgery, further treatment was associated with improved survival. Patients with OAML might experience disease progression or relapse more than five years after initial treatment.
P352: SYMPTOMATIC VTE INCIDENCE IN ADULT ALL TREATED WITH PEG-ASPARAGINASE COMPARED TO THE NATIVE L-ASPARAGINASE IN WITH AN ASPARAGINASE-BASED PROTOCOL
Authors: R. Chen, J. Seki, L. Liu, E. Atenafu, K. Yee, A. Schuh, V. Gupta, S. Chan, A. Schimmer, D. Maze, M. Minden, H. Sibai
Journal: HemaSphere (2022)

Background: Venous thromboembolism (VTE) is a well-known complication in adults receiving aspraginase (ASNase)-based chemotherapy for adults in acute lymphoblastic leukemia, including the ASNase-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol. Previous studies have shown an VTE incidence of up to 41% in patients receiving the DFCI protocol and up to 29% with prophylactic anticoagulations. Since 2019, native L-asparaginase is no longer available in the Canada such that pegylated (PEG)-ASNase has gradually replaced native e.coli ASNase (L-ASNase) as part of the DFCI protocol at our centre. Aims: The object of this study is to evaluate the incidence of VTE between patients who received PEG-ASNase vs L-ASNase, with emphasis on the highest risk periods of induction and intensification phases. Methods: A single centred retrospective cohort study of 249 adult patients with Philadelphia chromosome negative (Ph-) between 2011 to 2021 were conducted. There were 178 patients received L-ASNase between 2011 to 2019 and 71 patients received PEG-ASNase between 2018-2021. Of note, all patients received enoxaparin for DVT prophylaxis during the intensification phase. Results: During the induction phase, 19 out of 178 (10.6%) patients who received L-ASNase during induction developed VTE, whereas 21 out of 71 (29.6%) patients with PEG-ASNase developed VTE (p-value = 0.0002, OR = 3.079, 95 CI 1.43-6.64), with multivariable analysis after adjusting for age, sex, weight, and central line types. Similarly, during the intensification phase, 19 out of 135 (14.1%) patients had VTE on L-ASNase while 10 out of 34 (29.4%) patients on PEG-ASNase developed VTE (p-value =0.014, OR= 2.94, 95% CI 1.21-7.13) after adjusting for age, sex, weight, and central line types. Of note, PICC line was noted to be associated with higher incidence of CVC lines with during induction (p-value= 0.021, OR= 2.52, 95% CI 1.15-5.51). Image:Summary/Conclusion: PEG-ASNase is associated with higher incidence of VTE compared to L-ASNase, both during induction and intensification, despite the administration of prophylactic anticoagulation. Further investigations and strategies on reducing VTE risk associated with PEG-ASNase is needed in adult ALL patients who receive an asparaginase-based protocol.
P334: CHARACTERIZATION OF A DUX4-R INHIBITOR AS A POSSIBLE TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: S. Mara, V. Runfola, M. Pannese, C. Caronni, R. Giambruno, D. Campolungo, C. Ghirardi, D. Gabellini
Journal: HemaSphere (2022)

Background: Acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer and the major cause of cancer-related death before the age of 20. In up to 10% of cases, the disease is caused by translocation of the Double Homeobox 4 (DUX4) transcription factor to the immunoglobulin heavy chain (IGH) locus, giving rise to rearranged DUX4 (DUX4-r), maintaining the DNA binding domain (dbd) but with a rearranged C-terminus. Contrary to wild type DUX4, which induces apoptosis, DUX4-r acquires transforming ability in cellular and animal models. Through proteomics, we identified a potential DUX4-r inhibitor (iD) for its ability to bind directly to DUX4-r dbd. Aims: The goal of my project is to test the antileukemic potential of iD in cellular and animal models of DUX4-r leukemia. Methods: Human and murine cell lines and primary murine bone barrow progenitor cells are lentivirally-transduced to induce the expression of DUX4-r alone or in combination with iD, and the effects on proliferation, transformation, and B lymphoid differentiation potential are being evaluated. To establish a B-ALL model, DUX4-r PDX cells have been expanded in NSG mice. These cells have been transduced with GFP or iD fused to GFP (GFP-iD) and injected into new NSG recipients for expansion. Serial xenograft transplantation of the purified transduced cells have been performed to test iD-dependent effect on PDX cells expansion and leukemia latency in mice. Human markers and GFP expression were monitored over time in peripheral blood (PB) to assess disease progression. Results: We confirmed that DUX4-r can transform NIH-3T3 murine fibroblasts and inhibits B-cell differentiation of primary murine bone marrow progenitor cells in vitro. We found that iD decreases DUX4-r dependent transactivation. Moreover, lentiviral expression of iD in B-ALL NALM6 cells (carrying an endogenous DUX4-r translocation) reduces the levels of DUX4-r targets and impairs cell proliferation compared to transduced control cells. Preliminary results show that PDX cells expressing GFP-iD expand less and have a delayed PB engraftment compared to GFP control cells. Moreover, we noticed that in iD cohort only contaminant GFP-ve PDX cells take over in vivo despite purification by FACS sorting of transduced cells. Summary/Conclusion: So far, iD expression is associated with reduced proliferation of human DUX4-r leukemia cells and reduced DUX4-r targets expression. Pre-clinical validation of iD could identify effective therapeutic approaches for the treatment of DUX4-r B-ALL patients.
SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1
Authors: Shilei Zhang, Jingfeng Wang, Lulan Wang, Saba Aliyari, Genhong Cheng
Journal: Cellular and Molecular Immunology (2022)

Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome (ARDS)-related respiratory failure. Cytokine storms and oxidative stress are the major players in ARDS development during respiratory virus infections. However, it is still unknown how oxidative stress is regulated by viral and host factors in response to SARS-CoV-2 infection. Here, we found that activation of NRF2/HMOX1 significantly suppressed SARS-CoV-2 replication in multiple cell types by producing the metabolite biliverdin, whereas SARS-CoV-2 impaired the NRF2/HMOX1 axis through the action of the nonstructural viral protein NSP14. Mechanistically, NSP14 interacts with the catalytic domain of the NAD-dependent deacetylase Sirtuin 1 (SIRT1) and inhibits its ability to activate the NRF2/HMOX1 pathway. Furthermore, both genetic and pharmaceutical evidence corroborated the novel antiviral activity of SIRT1 against SARS-CoV-2. Therefore, our findings reveal a novel mechanism by which SARS-CoV-2 dysregulates the host antioxidant defense system and emphasize the vital role played by the SIRT1/NRF2 axis in host defense against SARS-CoV-2.
Portable HEPA Filter Air Cleaner Use during Pregnancy and Children’s Cognitive Performance at Four Years of Age: The UGAAR Randomized Controlled Trial
Authors: Battsetseg Ulziikhuu, Enkhjargal Gombojav, Chimeglkham Banzrai, Sarangerel Batsukh, Enkhtuul Enkhtuya, Buyantushig Boldbaatar, David C. Bellinger, Bruce P. Lanphear, Lawrence C. McCandless, Sukhpreet K. Tamana, Ryan W. Allen
Journal: Environmental Health Perspectives (2022)

Background: Developmental exposure to air pollution is associated with diminished cognitive abilities in observational studies, but no randomized controlled trial has examined the effect of reducing air pollution on cognition in children. Objectives: We sought to quantify the impact of reducing exposure to particulate matter (PM) during pregnancy on children's cognitive performance at 4 y of age. Methods: In this single-blind, parallel-group, randomized controlled trial in Ulaanbaatar, Mongolia, we randomly assigned 540 nonsmoking pregnant women (268 intervention and 272 control) to receive 1–2 portable high-efficiency particulate air (HEPA) filter air cleaners or no air cleaners. The air cleaners were used from a median of 11 wk gestation until the end of pregnancy. The primary outcome was full-scale intelligence quotient (FSIQ) assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when children were a median of 48 months old. We imputed missing outcome data using multiple imputation with chained equations, and our primary analysis was by intention to treat. Results: After excluding known miscarriages, stillbirths, neonatal deaths, and medical conditions that impeded cognitive testing and imputation, 475 (233 control and 242 intervention) children were included in our analyses. In an unadjusted analysis, the mean FSIQ of children who were randomly assigned to the intervention group was 2.5 points [95% confidence interval (CI): −0.4, 5.4 points] higher than that of children in the control group. After adjustment to account for an imbalance in preterm birth between groups, the effect estimate increased to 2.8 points (95% CI: −0.1, 5.7). Conclusions: Reducing PM air pollution during pregnancy may improve cognitive performance in childhood. https://doi.org/10.1289/EHP10302
Acetazolamide in Decompensated Heart Failure with Volume Overload trial (<scp>ADVOR</scp>): baseline characteristics
Authors: Wilfried Mullens, Jeroen Dauw, Pieter Martens, Evelyne Meekers, Petra Nijst, Frederik H. Verbrugge, Fabien Chenot, Samer Moubayed, Riet Dierckx, Philippe Blouard, David Derthoo, Walter Smolders, Bavo Ector, Michaël Hulselmans, Stijn Lochy, David Raes, Emeline Van Craenenbroeck, Hans Vandekerckhove, Pieter‐Jan Hofkens, Kathleen Goossens, Anne‐Catherine Pouleur, Michel De Ceuninck, Laurence Gabriel, Philippe Timmermans, Edgard A. Prihadi, Frederik Van Durme, Michel Depauw, Delphine Vervloet, Els Viaene, Jean‐Luc Vachiery, Katrien Tartaglia, Jozine M. ter Maaten, Liesbeth Bruckers, Walter Droogne, Pierre Troisfontaines, Kevin Damman, Johan Lassus, Alexandre Mebazaa, Gerasimos Filippatos, Frank Ruschitzka, Matthias Dupont
Journal: European Journal of Heart Failure (2022)
P471: ERYTHROID/MEGAKARYOCYTIC DIFFERENTIATION BIAS IN BONE MARROW OF AML/MDS PATIENTS AFTER DECITABINE TREATMENT
Authors: F. Tiso, A. O. de Graaf, L. I. Kroeze, B. A. van der Reijden, S. M. C. Langemeijer, K. M. Hebeda, J. H. Jansen
Journal: HemaSphere (2022)

Background: The hypomethylating agent Decitabine is used mainly in AML patients who are not eligible for standard induction chemotherapy or as a bridge therapy before a stem cell transplantation. Decitabine is an analogue of cytidine deoxynucleoside and it is incorporated into the DNA as decitabine triphosphate. In the DNA decitabine triphosphate inhibits the methylation of the DNA, leading to the reactivation of tumour suppressor genes which have been epigenetically silenced, induces cell differentiation and also apoptosis. Aims: We studied early signs of morphological changes in bone marrow biopsies (BMB) of AML/MDS patients after treatment with Decitabine and correlated these with the mutational background. Methods: We investigated 45 patients with AML/MDS who were treated with Decitabine. Bone marrow biopsies were morphologically examined, and we assessed the mutational status of the BMB. Sequencing was performed using a panel of 27 commonly mutated genes in myeloid malignancies, using a targeted error corrected approach. Results: We observed a striking erythroid/megakaryocytic differentiation bias after treatment in 16/45 patients, whereas the other patient group (n=29) showed predominant myeloid differentiation. Patients developing this erythroid/megakaryocytic bias showed a trend towards a higher frequency of mutations in genes encoding for spliceosome components (U2AF1, SF3B1 and SRSF2), in particular U2AF1 was found significantly (p-value=0.05) more mutated. Furthermore, this group carried a significantly (p-value=0.03) lower number of mutations in genes encoding for proteins involved in signalling and kinase pathways (ETNK1, FLT3, CBL, JAK2, KIT, KRAS, MPL, BRAF, NRAS) compared to the group with predominant myeloid differentiation. Summary/Conclusion: A bias towards erythroid/megakaryocytic differentiation was observed in the bone marrow of one third of the patients after treatment with Decitabine. This bias was over-represented in patients with mutations in spliceosome component encoding genes, particularly U2AF1. Patients with myeloid predominant Decitabine response harboured an increased number of mutations in signalling and kinase proteins encoding genes.
P494: MYELOID LEUKEMIA IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES: A RETROSPECTIVE COHORT STUDY
Authors: A. Abomhya, A. Razzaq, S. Lukose
Journal: HemaSphere (2022)

Background: Inflammatory bowel diseases include ulcerative colitis and Crohn’s disease and affect around 3.1 million adults in the United States (US). The data on the risk of myeloid leukemia among patients with IBD are limited and there has been only a couple of studies that evaluated the incidence of myeloid leukemia in this patient population. Aims: This study aimed to estimate the prevalence of myeloid leukemia in patients with IBD. Secondary outcomes included mortality, length of stay, all-cause 30-day non-elective readmission rate, and total cost of hospitalization. Methods: This is a retrospective cohort study for patients with IBD in the US. We queried the Nationwide Readmission Databases 2016-2018 using ICD-10-CM codes to identify all adult patients admitted for IBD. Patients with a comorbid diagnosis of myeloid leukemia including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Myeloid sarcoma, and Unspecified Myeloid leukemia were identified. Figure 1 summarizes the case selection process. Median and IQR were used to describe Continuous variables, and proportions were used with categorical variables. Comparison between groups was performed by Mann Whitney test for continuous variables and Chi-Square test for Categorical variables. Multivariate regression analysis was performed to study the impact of comorbid myeloid leukemia on inpatient mortality and non-elective readmissions. Statistical analyses were performed using SPSS Version 25 (IBM Corporation, Armonk, NY, USA). Results: We extracted 365,152 index hospitalization records for IBD, 1052 (0.3%) had myeloid leukemia. Six hundred sixteen patients had acute myeloid leukemia (AML), 341 patients had chronic myeloid leukemia, 10 patients had myeloid sarcoma and 104 had unspecified myeloid leukemia. IBD patients with myeloid leukemia were older (64; Interquartile Range (IQR): 52-73 vs. 56; IQR: 38-70, P <0.001), more common to be males (50.8% vs. 49.2%, P <0.001) compared to IBD patients without myeloid leukemia. Having myeloid leukemia was associated with increased length of stays in days (7; Interquartile Range (IQR): 3-23 vs. 3; IQR: 2-6, P <0.001), increased median total charges ($74,413; IQR: $31,700 - $259,676 vs. $32,586; IQR: $17,827 - $62,260, P <0.001). On multivariate analysis; having myeloid leukemia was associated with increased mortality (Odds ratio (OR): 6.544; 95% confidence interval (CI): 5.318-8.052, P <0.001) and higher odds of all-cause 30-day non-elective readmission (OR: 1.4; 95% CI: 1.155-1.697, P= 0.001). Image:Summary/Conclusion: In our nationwide cohort of IBD patients, 0.3% had myeloid leukemia. Given the associated mortality and morbidity, we recommend considering a hematological consult for IBD patients with leukocytosis or leukopenia for further evaluation and appropriate management. More research studies are needed to investigate the pathogenesis of myeloid leukemia in IBD patients.